A. Head Trauma
Head injury is a trauma to the head, that may or may not include injury to the brain (see also brain injury). The incidence (number of new cases) of head injury is 300 per 100,000 per year (0.3% of the population), with a mortality of 25 per 100,000 in North America and 9 per 100,000 in Britain. Head trauma is a common cause of childhood hospitalization.
Head injuries include both injuries to the brain and those to other parts of the head, such as the scalp and skull. Head injuries may be closed or open. A closed (non-missile) head injury is one in which the skull is not broken. A penetrating head injury occurs when an object pierces the skull and breaches the dura mater. Brain injuries may be diffuse, occurring over a wide area, or focal, located in a small, specific area. A head injury may cause a skull fracture, which may or may not be associated with injury to the brain. Some patients may have linear or depressed skull fractures. If intracranial hemorrhage, or bleeding within the brain occurs, a hematoma within the skull can put pressure on the brain. Types of intracranial hematoma include subdural, subarachnoid, extradural, and intraparenchymal hematoma. Craniotomy surgeries are used in these cases to lessen the pressure by draining off blood. Head trauma is caused by a concussive event.
Brain injury can be at the site of impact, but can also be at the opposite side of the skull due to a contrecoup effect (the impact to the head can cause the brain to move within the skull, causing the brain to impact the interior of the skull opposite the head-impact). If the impact causes the head to move, the injury may be worsened, because the brain may ricochet inside the skull (causing additional impacts), or the brain may stay relatively still (due to inertia) but be hit by the moving skull.
B. Protein Kinase C
PKC has been identified as one of the largest gene families of non-receptor serine-threonine protein kinases. Since the discovery of PKC in the early eighties by Nishizuka and coworkers (Kikkawa et al. (1982) J. Biol. Chem. 257: 13341), and its identification as a major receptor for phorbol esters (Ashendel et al. (1983) Cancer Res., 43: 4333), a multitude of physiological signaling mechanisms have been ascribed to this enzyme. The intense interest in PKC stems from its unique ability to be activated in vitro by calcium and diacylglycerol (and its phorbol ester mimetics), an effector whose formation is coupled to phospholipid turnover by the action of growth and differentiation factors.
The activation of PKC has been shown to improve learning and memory. (U.S. patent application Ser. Nos. PCT/US02/13784; PCT/US03/07102; 60/287,721; 60/362,081; 10/172,005; and 10/476,459; each incorporated herein by reference in its entirety). Prior to the present disclosure, however, the PKC-mediated improvement of learning and memory has not been recognized as a mechanism for the treatment of post-head trauma memory deficits and brain injury. Also, the PKC activators disclosed herein, specifically those compounds that improve learning and memory, were not recognized as possessing brain function-restoring activity after head trauma.
Head trauma therapy has historically been limited to few treatment options available. Although many types of potential neuroprotectants have been tested in clinical trials, none has been approved for clinical use, because of ineffectiveness especially when used post-head trauma or associated toxicity. The compounds presented in this invention disclosure were effective when the treatment was started one hour after the head trauma in the animal model at doses that have already been demonstrated to be well tolerated in humans (the bryostatin-1 doses). Compounds that target the protein kinase C(PKC) such as bryostatin-1, a direct PKC activator, and methylcatechol diacetic acid, a derivative of methylcatechol, an enhancer of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or other neurotrophic factors, which is perhaps one of the PKC targets, have been found to have therapeutic value against brain injury and memory impairment induced with head trauma. The development of these substances as therapeutic in the treatment of head trauma is provided by this invention.